Total synthesis of sphingofungin F.

Article abstract of DOI:10.1021/ol020164f

[reaction: see text] A concise, stereocontrolled synthesis of sphingofungin F was achieved. Key features involve diastereoselective oxazoline formation catalyzed by palladium(0), MgBr(2)-promoted gamma-alkoxy allylic stannane addition, and palladium(0)-ca

Full text of DOI:10.1021/ol020164f

ORGANIC
LETTERS
2002
Vol. 4, No. 25
4403-4405
Total Synthesis of Sphingofungin F
Kee-Young Lee, Chang-Young Oh, and Won-Hun Ham*
College of Pharmacy, SungKyunKwan UniVersity, Suwon 440-746, Korea
whham@speed.skku.ac.kr
Received August 14, 2002
ABSTRACT
A concise, stereocontrolled synthesis of sphingofungin F was achieved. Key features involve diastereoselective oxazoline formation catalyzed
by palladium(0), MgBr2-promoted γ-alkoxy allylic stannane addition, and palladium(0)-catalyzed coupling of a vinyl iodide with an organozinc
reagent.
Sphingofungins E and F, potent antifungal agents possessing
a polar polyhydroxy amine group and long lipid chains, were
isolated from the fermentation broth of Paecilomyces Variotii
by a Merck group in 1992.1 These compounds have a
quaternary center, four consecutive chiral centers, and a trans
olefinic group in their polyhydroxy amine headgroups. Along
with other congeners (A-D), they were found to block the
biosynthesis of sphingolipid, leading to apoptosis in both
yeast and mammalian cells. These cellular effects are due
to their potent inhibitory activities against serine palmitoyl-
transferase (SPT), an essential committed enzyme involved
in the first step of sphingosine biosynthesis.2
The combination of their potent biological activity and
their novel structure has led to wide interest in the synthetic
community. The first total synthesis of sphingofungin F was
reported by Kobayashi and co-workers in 1998.5a Shortly
thereafter, Trost3b and Lin3c reported the completion of
sphingofungin F. On the basis of our previous research,4 we
anticipated that the palladium(0)-catalyzed oxazoline forma-
tion of homoallyl benzamide 10 formed from protected
Figure 1.
L-serinol 9 might proceed with high stereoselectivity. As part
of a program directed at expanding the synthetic utility of
oxazoline as a chiral building block for the synthesis of
natural products, we report herein our synthetic efforts, which
led to a concise and highly stereocontrolled total synthesis
of 1 using oxazoline 8. Our retrosynthetic analysis as shown
in Scheme 1 suggests that 1 may be synthesized by the
(1) Horn, W. S.; Smith, J. L.; Bills, G. F.; Raghoobar, S. L.; Helms, G.
L.; Kurtz, M. B.; Marrinan, J. A.; Frommer, B. R.; Thornton, R. A.;
Mandala, S. M. J. Antibiot. 1992, 45, 1693.
(2) Zweerink, M. M.; Edison, A. M.; Well, G. B.; Pinto, W.; Lester, R.
L. J. Biol. Chem. 1992, 267, 25032.
(3) (a) Kobayashi, S.; Matsumura, M.; Furuta, T.; Hayashi, T.; Iwamoto,
S. Synlett 1997, 301. (b) Kobayashi, S.; Furuta, T.; Hayashi, T.; Nishijima,
M.; Hanada, K. J. Am. Chem. Soc. 1998, 120, 908. (c) Kobayashi, S.; Furuta,
T.; Hayashi, T.; Nishijima, M.; Hanada, K. Tetrahedron 1998, 54, 10275.
(d) Trost, B. M.; Lee, C. B. J. Am. Chem. Soc. 1998, 120, 6818. (e) Liu,
D.-G.; Wang, B.; Lin, G.-Q. J. Org. Chem. 2000, 65, 9114. (f) Trost, B.
M.; Lee, C. B. J. Am. Chem. Soc. 2001, 123, 12191.
(4) (a) Lee, K.-Y.; Kim, Y.-H.; Park, M.-S.; Ham, W.-H. Tetrahedron
Lett. 1998, 39, 8129. (b) Lee, K.-Y.; Kim, Y.-H.; Park, M.-S.; Oh, C.-Y.;
Ham, W.-H. J. Org. Chem. 1999, 64, 9450. (c) Lee, K.-Y.; Kim, Y.-H.;
Oh, C.-Y.; Ham, W.-H. Org. Lett. 2000, 2, 4041.
(5) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Meyers, A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.; Lanman, B. A.;
Kwon, S. Tetrahedron Lett. 2000, 41, 1359.
10.1021/ol020164f CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/12/2002

Scheme 1
palladium-catalyzed coupling reaction of 2 with 3. A chiral
formation [Pd(PPh3)4, K2CO3 in CH3CN] of the allylic acetate
10 gave the desired trans-oxazoline 8 as a single diastereomer
in good yield (87%). No trace of the minor isomer could be
detected in a number of repeated experiments.
Deprotection of the silyl ether of oxazoline 8 gave the
alcohol. Oxidation of the primary alcohol proved to be
troublesome under a variety of conditions (e.g., Swern,7
PCC,8 Dess-Martin4b,5). Fortunately, oxidation with ruthe-
nium did provide the requisite carboxylic acid.9 The resulting
carboxylic acid was converted to its methyl ester 7 with
diazomethane in 68% yield (Scheme 3). The alkylation
quaternary carbon center could be constructed with the
desired stereochemistry via methylation of ester 7 readily
accessible from the protected L-N-benzoyl serinol 9 by our
newly developed palladium (0)-catalyzed oxazoline forma-
tion reaction. The pendant vinyl group could be converted
to the aldehyde, which could be employed in the diastereo-
selective cis-dihydroxylation using MgBr2-promoted γ-alkoxy
allylic stannane addition. It was also anticipated that 4 could
be converted to 2 in two steps (ozonolysis and Takai
reaction).
The synthesis of 1 began with the protected L-N-benzoyl
serinol 9 as shown in Scheme 2. Oxidation of alcohol 9 with
Scheme 3a
Scheme 2a
a Conditions: (a) (i) TBAF, THF, 99%; (ii) RuCl3, K2S2O8, 1
M NaOH, CH3CN; (iii) CH2N2, Et2O, 68% for two steps. (b) CH3I,
KHMDS, HMPA, THF, -78 °C, 73%. (c) (i) O3, MeOH, -78 °C,
then DMS; (ii) 6, MgBr2-Et2O, CH2Cl2, 78% for two steps. (d)
(i) O3, MeOH, -78 °C, then DMS; (ii) CrCl2, CHI3, THF, 63%
for two steps.
a Conditions: (a) (i) Dess-Martin periodinane, CH2Cl2; (ii)
CHdCHMgBr, THF, 0 °C, 70% for two steps. (b) Ac2O, pyr.,
CH2Cl2, 95%. (c) Pd(PPh3)4, K2CO3, CH3CN, 60 °C, 87%.
Dess-Martin periodinane4b,5 gave the corresponding alde-
hyde without racemization,4b,5b which was reacted with
vinylmagnesium bromide in THF at 0 °C to afford allyl
alcohol, as an ca. 1.1: 1 mixture of syn/anti isomers (1H
NMR) in 70% yield.6
reaction of 7 with MeI gave the anti alkylation product 5 as
the major isomer with high diastereoselectivity (20:1) and
in good yield (73%).10
Acetylation of the hydroxyl group yielded the secondary
allylic acetate 10. The palladium-catalyzed oxazoline ring
(7) (a) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978,
43, 2480. (b) Omura, K.; Swern, D. Tetrahedron 1987, 34, 1651.
(8) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 16, 2647.
(9) Green, G.; Griffith, W. P.; Hollinshead, D. M.; Ley, S. V.; Schroder,
M. J. Chem. Soc., Perkin Trans. 1 1984, 681.
(6) Denis, J.-N.; Correa, A.; Greene, A. E. J. Org. Chem. 1991, 56, 6939.
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Org. Lett., Vol. 4, No. 25, 2002

Ozonolysis of 5 gave the corresponding aldehyde. After
extensive investigation of a variety of protocols, we estab-
lished that when 1 equiv of aldehyde and 2.1 equiv of
MgBr2-OEt2 are treated with 3 equiv of stannane, protected
diol 4 was formed with >20:1 diastereoselectivity in 78%
yield after silica gel chromatography.11 This process ef-
ficiently adjusted the stereochemistry and provided simul-
taneous protection for the newly generated hydroxyl group.
The following steps to introduce the lipophilic side chain
into compound 4 were achieved by applying Trost’s method3d,f
with some variation.
Scheme 4a
Ozonolysis and iodomethylenation of 4 with low-valent
chromium generated (E)-alkene 2 exclusively.3d,f,12 Although
the coupling of the side chain by a Suzuki reaction13 was
well established, we tried a different coupling process using
Negishi’s protocol14 and verified that it could be applied
successfully as a surrogate reaction. Palladium(0)-catalyzed
coupling of 2 with the alkyl zinc generated from iodide 315
provided the fully protected 11 in 68% yield (Scheme 4).14
Acid-catalyzed hydrolysis of 11 gave lactone. Finally, a
base-promoted hydrolysis cleaved the lactone and the amide
groups, and subsequent neutralization with an acidic resin
a Conditions: (a) 3, t-BuLi, -78 °C; then, ZnCl2, from -78 °C
to rt, Pd(PPh3)4, THF, 68%. (b) 2 N HCl, THF, 80%. (c) 1 N NaOH,
reflux, 79%.
(Amberlite IRC-76) afforded sphingofungin F (1). The
synthetic compound was spectroscopically in good agreement
with the natural and synthetic sphingofungin F. Our [R]D of
+0.8 (c 0.25, CH3OH) compared to the reported [R]D +0.8
(c 0.33, CH3OH)3a confirms the identity of the absolute
configuration.
(10) Berkowitz, D. B.; McFadden, J. M.; Chisowa, E.; Semerad, C. L.
J. Am. Chem. Soc. 2000, 122, 11031.
(11) For reviews, see: (a) Marshall, J. A. Chem. ReV. 1996, 96, 31. (b)
Marshall, J. A. Chem. ReV. 2000, 100, 3163.
In summary, we report a new asymmetric synthetic method
for sphingofungin F utilizing oxazoline 8. The key features
in this strategy are the diastereoselective oxazoline formation
reaction catalyzed by palladium(0), MgBr2-promoted γ-alkoxy
allylic stannane addition, and palladium(0)-catalyzed cou-
pling of vinyl iodide with organozinc reagent. With the same
protocol, our synthesis of sphingofungin E is in progress.
(12) (a) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408. (b) Kende, A. S.; DeVita, R. J. Tetrahedron Lett. 1990, 31, 307. (c)
Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497. Due to the
presence of R-branching in the precursor aldehydes, high proportions of
the (E)-alkenes were obtained without the use of dioxane.
(13) (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314. (b) Johnson, C. R.; Braun,
M. P. J. Am. Chem. Soc. 1993, 115, 11014. (c) Miyaura, N.; Suzuki, A.
Chem. ReV. 1995, 95, 2457. (d) Ohba, M.; Kawase, N.; Fujii, T. J. Am.
Chem. Soc. 1996, 118, 8250.
(14) (a) Erdik, E. Tetrahedron 1992, 48, 9577. (b) Negishi, E.; Ay, M.;
Culevich, Y. V.; Noda, Y. Tetrahedron Lett. 1993, 34, 1437. (c) Williams,
D. R.; Kissel, W. S. J. Am. Chem. Soc. 1998, 120, 11198.
(15) Preparation of alkyl iodide:a
Acknowledgment. This study was supported by a grant
of the Korea Health 21 R&D Project, Ministry of Health
and Welfare, Republic of Korea (01-PJ1-PG1-01CH13-
0002).
Supporting Information Available: Experimental pro-
cedure and characterization data for compounds 1-11. This
material is available free of charge via the Internet at
http://pubs.acs.org.
aConditions: (i) NH(CH3)OCH3-HCl, pyr., CH2Cl2, 92%; (ii) CH2dCH-
(CH2)5CH2MgBr, THF, 93%; (iii) ethylene glycol, PTSA, PhH, 90%; (iv)
O3/MeOH, then NaBH4, 92%; (v) I2, PPh3, CH2Cl2, 87%.
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